Diabetes is a chronic disease caused by dysbolism leading to chronic hyperglycemic state by insufficient action of insulin. Diabetes is grouped into Type 1 diabetes characterized by insufficient secretion of insulin and Type 2 diabetes characterized by lowered secretion of insulin and lowered sensitivity (insulin resistance). In particular, Type 2 diabetes, which accounts for 90 to 95% of diagnosed diabetes, is said to be closely correlated with contemporary life-style diseases, such as obesity, hypertension, hyperlipemia and metabolic syndrome.
Known diabetes drugs include sulfonylureas, phenylalanine derivatives, α-glucosidase inhibitors, biguanides, thiazolidine derivatives and the like, but use of these drugs is restricted, because of accompanied adverse reaction such as severe hypoglycemia, gastrointestinal tract disorder, liver function disorder or lactic acidosis. In addition, sulfonylureas and thiazoline derivatives are known to accelerate increase of body weight (Japan Diabetes Society Ed., “Diabetes Treatment Guide 2008-2009,” 2008).
Obesity, which is in the state where energy is stored abnormally in adipose tissue by overeating and lack of exercise, can cause Type 2 diabetes and also hypertension, heart disease and others.
Anti-obesity drugs include Mazindol, Orlistat, Rimonabant and the like. Mazindol has primary pharmacologic actions of central suppression of feeding and acceleration of heat production in peripheral organs, but is often accompanied with central adverse reactions such as nausea, headache and dizziness and, thus, strict control is needed for its use. Orlistat suppresses fat absorption and thus leads to decrease of body weight by inhibiting lipases, but it also inhibits absorption of lipophillic vitamins and, thus, vitamins should be supplemented, as needed. Rimonabant suppresses appetite and leads to decrease of body weight by interaction with cannabinoid 1 receptor, but has a problem of central adverse reactions such as dizziness, nausea and headache. These anti-obesity drugs have not only action to reduce body weight but also various disadvantages and adverse reactions and, for that reason, there exists a need for development of an anti-obesity drug that is more effective and superior in efficiency in use (Japan Pharmaceutical Information Center Ed., “Medical Drugs 2008,” 2007, Takahashi et al., Igakuno Ayumi, Vol. 213, No. 6, 2005, p 549 and Saiki et al., Igakuno Ayumi,” Vol. 213, No. 6, 2005, p 643).
Dyslipidemia is a disease accompanied with abnormality in blood cholesterol and tri-glyceride levels. Dyslipidemia results in arteriosclerosis, further leading to increase of the risks of coronary disease such as angina cordis and myocardial infarction. Anti-dyslipidemia drugs are drugs for reduction of the blood triglyceride and LDL cholesterol levels that are important for prevention of coronary diseases (Kinoshita, Saishin Igaku, Vol. 63, No. 2, 2008, p 7).
Anti-dyslipidemia drugs include statins (HMG-CoA reductase inhibitor) such as pravastatin and atrovastatin; bile acid absorbents such as cholestyramine and cholestimide; fibrates such as clofibrate and bezafibrate; and the like. Statins occasionally cause adverse reactions such as digestive organ symptoms and rhabdomyolysis. Bile acid absorbents have adverse reactions such as constipation and abdominal bloating and occasionally inhibit absorption of drugs used in combination. Fibrates should be used carefully with caution to the adverse reactions such as rhabdomyolysis and liver function disorder. All of these anti-dyslipidemia drugs have action to decrease serum triglyceride or cholesterol level, but, in fact, they also have various disadvantages and adverse reactions (Japan Pharmaceutical Information Center Ed., “Medical Drugs 2008,” 2007).
Metabolic syndrome is a syndrome in combination of some of abdominal obesity, hypertriglyceridemia, hypo-HDL-cholestrolemia, hyperglycemia and hypertension, and it is considered to be a syndrome higher in the risk of arteriosclerotic diseases, because these symptoms in combination leads to increase of the risk of arteriosclerotic diseases.
As for the diagnostic standard of metabolic syndrome, for example, National Cholesterol Education Program (hereinafter, NCEP) in 2001 defines, as the metabolic syndrome, a syndrome that have values higher than standards at least in three risk factors among the risk factors 1 to 5 shown in Table 1. The International Diabetes Federation (hereinafter, IDF) and the Examination Committee of Criteria for Obesity Disease in Japan (joint committee of eight academic societies including Japan Atherosclerosis Society, Japan Diabetes Society and others) define, as the metabolic syndrome, a syndrome showing abdominal obesity as essential item and additionally multiple items selected from hypertriglyceridemia, hypo-HDL-cholesterolemia, hypertension and hyperglycemia. Because the risk factors are treated only individually in chemical treatment of metabolic syndrome, there exists a need for a drug that is effective to multiple risk factors even as a single drug (Hirata et al., Saishin Igaku, Vol. 61, No. 3 (Special Issue), 2006, p 579 and Okada et al., Saishin Igaku, Vol. 63, No. 2, 2008, p 262).
TABLE 1Standard for diagnosis of metabolic syndrome (NCEP Standard)Risk factorStandard1.Abdominal circumferencemale>102cmfemale>88cm2.Triglyceride≧150mg/dl3.HDL cholesterolmale<40mg/dlfemale<50mg4.Blood pressureSystolic blood pressure≧130mmHgand/orDiastolic blood pressure≧85mmHg5.Fasting blood sugar≧110mg/dl
Under the circumstance above, β3 adrenoreceptor agonists have been proposed as a new drug candidate to type 2 diabetes and obesity (Washburn et al., Bioorg. Med. Chem. Lett., Vol. 11, 2001, p 3035 and Harada et al., Chem. Pharm. Bull., Vol. 53, 2005, p 184). The β3 adrenoreceptors present in the fat cells of rodents and humans are suggested as having an important role in regulation of fat decomposition and heat production (Howe, Drug Future, Vol. 18, 1993, p 529 and Arch et al., J. Med. Res. Rev., Vol. 13, 1993, p 663). Functional deterioration of β3 adrenoreceptor results, for example, in accumulation of body fat and, thus, its correlation with development of obesity is suggested (Revelli et al., J. Clin Invest., Vol. 100, 1997, P 1098). However, development of a β3 adrenoreceptor agonist as diabetes drug is so far unfruitful, because of the adverse reactions on the cardiovascular system.
JP-A 7-206806 discloses a β3 adrenoreceptor agonist (amine derivative). However, there is no disclosed pharmacological data showing the efficacy thereof to diabetes and obesity.
Washburn et al., Bioorg. Med. Chem. Lett., Vol. 11, 2001, p 3035 discloses the following benzylamine derivative (1) as a β3 adrenoreceptor agonist. However, the data available concerning the efficacy thereof to diabetes and obesity is only limited to the action of decomposing free fatty acids.

No drug is developed from the benzylamine derivative (1) above and analogous benzylamine derivatives, which are β3 adrenoreceptor agonists, because there are adverse reactions on the cardiovascular system (prolongation of QT interval and increase of heart rate) (Washburn et al., Bioorg. Med. Chem. Lett., Vol. 11, 2001, p 3035 and Gavai et al., Bioorg. Med. Chem. Lett., Vol. 11, 2001, p 3041).
Alternatively, U.S. Pat. No. 3,341,584 discloses a wide range of compounds including part of the benzylamine derivatives (1) above. However, usefulness of these compounds to diabetes, obesity, dyslipidemia or metabolic syndrome is currently unknown.
Thus, it could be helpful to provide a therapeutic or prophylactic agent for diabetes, obesity, dyslipidemia or metabolic syndrome, which can exhibit significant efficacy at lower dose and does not have an increase of heart rate or a prolongation of QT interval which is an adverse side effect on the cardiovascular system.